Lung cancer is the leading cause of cancer-related death in the United States and is responsible for over 160,000 patient deaths from their lung cancer this year, more than that of breast, colorectal, prostate, colon and other cancers combined. With the existing therapeutic efforts, patients with lung cancer have a 5-year survival rate of less than 15%. There is a tremendous unmet need for treatment of Non-Small-Cell lung cancer, represent 85% of all lung cancer patients. Efforts have recently been directed toward developing novel therapies based on a growing understanding of molecular oncology. Understanding the molecular mechanisms involved in the pathogenesis of lung cancer can provide opportunities to develop innovative therapies for NSCLC. In this proposal, we proposed a novel multi-targeted siRNA therapeutic for NSCLC treatment. We will test this drug candidate in A549 and H460 xenograft tumor models for its antitumor efficacy and safety profiles. We will also use HKP and PTL nanoparticle to further enhance the this siRNA cocktail therapeutics, targeting EGFR, VEGF, Cox-2 or PDGF oncogenic genes. Furthermore, we test this drug in combination with current targeted therapeutics of small molecules and monoclonal antibodies, such as Tarceva, Iressa and Avastin, in the animal models, for an alternative therapeutics to treat NSCLC. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer-related death in the United States and is responsible for over 160,000 patient deaths from their lung cancer this year, more than that of breast, colorectal, prostate, colon and other cancers combined. There is a tremendous unmet need for treatment of Non-Small-Cell lung cancer, represent 85% of all lung cancer patients. In this proposal, we use a novel RNAi technology approach to develop a multi-targeted siRNA therapeutics for NSCLC treatment. The HKP and PTL nanoparticle technologies will greatly enhance systemic delivery of this siRNA cocktail therapeutics, targeting EGFR, VEGF, Cox-2 or PDGF oncogenic genes. Combining this siRNA drug with current targeted therapeutics of small molecule and monoclonal antibodies will provide us a powerful weapon to fight this deadly disease, NSCLC.